Trospium has been shown to reduce bladder hyperactivity in patients suffering from urinary incontinence and exerts spasmolytic effects on the bladder by inhibiting the effects of acetylcholine on smooth muscle. Thus, Trospium Chloride is an anticholinergic drug. Trospium Chloride has selectivity for muscarinic receptors over nicotinic receptors and as a result, no blocking effects are observed at skeletal neuromuscular junctions. Thus, the anticholinergic drug Trospium Chloride can also be called an antimuscarinic drug. Active metabolites of Trospium Chloride exert antimuscarinic activities that are believed to account for part of the therapeutic activity of trospium.
The terms ‘anticholinergic’ and ‘antimuscarinic’ are interchangeable in this document.
The terms ‘Memory Disorders’ and ‘memory disorders’ are interchangeable in this document.
The terms “predisposed” (to memory disorder) and “propensity” (for developing memory disorders), which are interchangeably used herein, refer to individuals who are at risk for developing Memory Disorders.
The term “urge incontinence” is in this document includes “over-active bladder” (OAB) and includes the disease called pollakiuria (frequent urinations).
Individuals who are predisposed to memory disorder may suffer from intermittent or “on and off” expression of memory disorders. After being diagnosed, memory disorders may also be intermittent, or appear “on-and-off” in patients; thus patients suffering from memory disorders may have symptoms that alternate between more or less severe.
Memory is the ability of the brain to retain and recall information.
Anti-cholinergic drugs are known to cause impairment of memory (Katz I. R., et al., J Am Geriatr Soc 1998, 46: 8-13). The leading drugs for Alzheimer's disease are cholinergic drugs, such as cholinesterase inhibitors, which have the opposite effect of common anticholinergic drugs, such as for example oxybutynin. Examples of cholinergic drugs that are used to improve memory functions are tacrine, (Cognex®, Pfizer); galantamine, (Reminyl®, Janssen); revastigmine, (Exelon®, Novartis) and donepezil, (Aricept®, Pfizer). Furthermore, withdrawal of anticholinergic medication usually causes immediate improvement of memory (Mori K., et al. Pharmacopsychiatry 2002, 35: 6-11).
Memory disorders can be of different types, such as Mild Impairment of Memory (including for examples forgetfulness and difficulty in remembering names), Amnesia (memory disorder affecting recollection of recent events), and Dementia (memory disorders affecting recollection of both recent and distant events). Alzheimer's Disease (AD) and Vascular Dementia (VaD) are the two leading causes of dementia in the elderly, with AD being the most prevalent type). A common type of memory disorders in the elderly is Senile Dementia, with various sub-forms, such as for example pre-senile dementia, which can be diagnosed in individuals that most often are of the age 65 years or older. In the case of pre-senile dementia, the disorder is often diagnosed in patients younger than 65 years of age. Thus, memory impairment can be a symptom of any of the aforementioned memory disorders.
While local concentrations of acetylcholine in the basalis magnocellularis of the forebrain are important for cognition, the physiological/anatomical basis for recollection (memory) is far less obvious. It is also very likely that short-term memory functions are different from long-term memory functions. Thus AD patients often have vivid long-term memory, but severe lack of short-term memory. It is obvious to those skilled in the art that cholinergic mechanisms are involved in memory functions, although it cannot of course be excluded that other neurotransmitters in the brain may also be involved. Basic and clinical studies have revealed that memory dysfunction in patients suffering from Alzheimer's disease is correlated with low concentrations of acetylcholine in the brain.
Memory disorders are usually diagnosed when a patient complains of memory loss. While a sophisticated diagnosis is usually made by a specialist, general practitioners often rely on specific diagnostic criteria. Physicians have also found The Mini-Mental State Examination (MMSE) to be useful for the diagnosis of certain forms of memory disorders, such as for example dementia. (Santacruz K. S., Swagerty D.: Early diagnosis of Dementia. Am Fam Physician 2001; 63: 703-713) . The MMSE shall only be performed by qualified medical personnel, and the test can be purchased by physicians from PAR Customer Support, 16204 N. Florida Avenue, Lutz, Fla. 33549. However, patients suffering from Mild Memory Impairment often perform like normal elderly persons and when given the MMSE, their score is usually 24 or higher, but they perform worse than normal individuals when tested for verbal and spatial memory (Brandt J. Am Fam Physician 2001, Vol. 63: Number 4, Editorial).
Test exist that can be used instead of the MMSE or in conjuncture with the MMSE. Furthermore, experienced physicians may be able to diagnose memory disorders without the help of a standardized test.
It is a method of the present invention to determine if patients, who are suffering from smooth muscle disorders, are simultaneously suffering from or having a propensity for developing memory disorders and if said determination is positive, administering to said patients a therapeutically effective amount of trospium or an active metabolite thereof or a pharmaceutically acceptable salt or solvate thereof. Said determinations can be performed by a physician using interviews, physical examination and/or application of a standardized test, such as for example the Mini-Mental State Examination (MMSE). While it is fairly easy to determine if a patient suffers from a memory disorder, it can be more difficult to determine if a patient is predisposed for the development of a memory disorder. While the ultimate ability to make this diagnose depends on the experience of the physician, age is most often considered to be a risk factor for the development of memory disorders. Other risk factors are for example cerebral atherosclerosis, untreated hypertension, alcohol or illegal drug abuse. It is possible that hereditary factors can be involved.
It is well known to those skilled in the art of psychiatric health care that anticholinergic drugs have a worsening effect on memory function in patients suffering from memory disorders and said types of drugs may induce memory disorders in patients who are predisposed to memory disorders or in patients who are at an early stage in the development of a memory disorder.
To have a direct effect on certain areas of the brain, drugs have to cross the blood-brain barrier (BBB). This barrier is made up of layers of cells, surrounding the small blood vessels that supply the brain with oxygen and nutrition. The BBB was previously believed to be a simple mechanical barrier, keeping all large molecules and all charged molecule out of the brain. Thus, factors believed to influence the ability of drugs to cross the blood-brain barrier were believed to include ionization (pKa), lipophilicity (log P) and molecular weight (MW). However, the knowledge about the nature of the BBB, its functions and its limitations have improved tremendously and it is now known that the BBB is not simply a mechanical barrier, but also has mechanisms in place for the active transport of molecules out of the brain. The BBB can become “leaky” (more permeable) of numerous reasons, such as for example by influence from the hormone epinephrine that is known to cause leakage of the BBB, thereby making it possible for various molecules to pass through the BBB and enter into the brain. Diseases, such as cognitive disorders, type-II diabetes and hypertension are often correlated with increased permeability of the EBB. It is also known that certain drugs can induce increased permeability of the BBB. Examples of such drugs are certain angiotensin converting enzyme inhibitors and phenylephrine. It is also well-known that the bloodbrain barrier deteriorates with age (Toornvliet J R, et al. J Cerebral Blood Flow & Metabolism, 2005, 25: 273; Bronge L, et. al. Dement Geriatr Cogn Disord, 2000, 11:263-267.) This is of importance in connection with the pharmacology of drugs for geriatric diseases like urinary urge incontinence, which almost exclusively affect the elderly. Acute studies on blood-brain barrier in healthy young volunteers (with healthy and well functioning BBB) are of no or very limited relevance to the elderly patients who are suffering from various chronic disorders, such as for example urinary urge incontinence (Todorova A, B, J Clin Pharmacol. 2001; 41:636-644). In general, quaternary amines penetrate the healthy BBB less readily than tertiary amines, however, quaternary amines are known to cross the BBB, even in healthy individuals. Thus, as a well-known example, the quaternary choline esterase inhibitor pyridostigmine was able to penetrate the BBB in American soldiers, causing the Persian Gulf Syndrome (PGS) in gulf war soldiers (Haley et al. JAMA, 1977, 277: 223-230.) Numerous other quaternary cholinergic drugs are known to cross the BBB and cause CNS-related side effects, such as for example the quaternary drugs edrophonium that causes convulsions and restlessness and neostigmine that causes dizziness, convulsions, drowsiness and headache and hyoscine (Buscolysin®, Sopharma) that has side effects such as anxiety and hallucinations.
Furthermore, the BBB is absent from significant parts of the brain, such as for example the hypothalamus, the pituitary and pineal areas, area postrema and areas of the choroids plexus.
It can be assumed that quaternary compounds, such as trospium will be able to cross the blood-brain barrier rather slowly in healthy and young individuals, but in elderly individuals and particularly in elderly patients with existing diseases, quaternary compounds have the ability to cross the blood-brain barrier. The reason why trospium does not have negative effects on memory and why trospium does not aggravate existing memory disorders is unknown.
To our knowledge, no known reference teaches or enables the methods of the present invention comprising administering trospium to a human suffering from Memory Disorders or being at risk for developing Memory Disorders; nor do the published references alone or in combination suggest these methods. It is of importance to note that many patients in earlier stages of Memory Disorders, express memory malfunctions that have a tendency to be intermittent or “come and go”. Elderly patients are considered to be at increased risk for developing memory disorders of various types.